Drugs that target oncogenic proteins, such as the rapidly accelerated fibrosarcoma (RAF) family kinase BRAF, frequently only elicit partial tumor regression, and tumor recurrence is common. Factors secreted by the stromal cells or immune cells within the tumor may contribute to drug resistance. Straussman et al. tested whether coculturing cancer cells lines with stromal cell lines would affect drug resistance of the cancer cells. Using a high-throughput microscopy method, they tested the proliferation of a panel of 45 fluorescently labeled human cancer cell lines cultured alone or in combination with 23 human stromal cell lines in the presence or absence of 35 anticancer drugs. Multiple melanoma cell lines with the constitutively active BRAF(V600E) exhibited proliferation and thus resistance to RAF inhibitor PLX4720 when cultured with one of six fibroblast cell lines. Exposure of the melanoma cell lines to fibroblast-conditioned medium also produced resistance, indicating that a secreted soluble factor was responsible. An antibody-array–based analysis of 567 secreted factors identified hepatocyte growth factor (HGF), an activator of the receptor tyrosine kinase (RTK) MET, as the factor that best correlated with PLX4720 resistance. Recombinant HGF caused drug resistance, whereas HGF-neutralizing antibodies or a MET inhibitor reversed resistance. HGF conferred to melanoma cell lines resistance not only to inhibitors of RAF but also to inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK). Analysis of biopsy samples from patients with BRAF(V600E) melanoma for HGF abundance by immunohistochemistry in tumor-associated stromal cells before treatment with RAF, MEK, or a combination of both inhibitors showed that patients with abundant HGF in their stromal cells correlated with a poor response to any of the inhibitor treatments. In an accompanying paper, Wilson et al. reported similar results with BRAF-mutant melanoma cell lines and found an inverse relationship between plasma HGF concentration and response to inhibitor treatment in patients with BRAF-mutant melanoma. Straussman et al. and Wilson et al. both determined that HGF treatment of cancer cells led to phosphorylation of not only MEK pathway effector ERK but also phosphatidylinositol 3-kinase (PI3K) pathway effector AKT. Straussman et al. found that inhibition of both MEK and AKT was effective at blocking proliferation of the melanoma cell lines and that combining RAF inhibitors and a MET inhibitor had a synergistic effect, significantly decreasing both MAPK and PI3K pathway activation. Together, these two studies suggest that tumor resistance to drugs inhibiting a kinase in one proliferation-promoting pathway can result from stromal signals that activate tumor receptors to stimulate alternative proliferation pathways.